European journal of cancer | 2021
Encorafenib, binimetinib plus pembrolizumab triplet therapy in patients with advanced BRAFV600 mutant melanoma: safety and tolerability results from the phase I IMMU-TARGET trial.
Abstract
BACKGROUND\nCombination of immune checkpoint inhibitors and mitogen-activated protein kinase (MAPK) pathway inhibitors (MAPKi) has been proposed to enhance the durability of anti-tumour responses induced by MAPKi. Here, we present phase I safety results from an open-label, phase I/II study of pembrolizumab (PEM), encorafenib (ENC) and binimetinib (BIN) triplet therapy in advanced, B-Raf proto-oncogene serine/threonine kinase (BRAF)V600-mutated melanoma (IMMU-TARGET, NCT02902042).\n\n\nMETHODS\nThe dose finding phase I part used a 3\xa0+\xa03 design, starting with the approved doses of PEM (200\xa0mg every three weeks), ENC (450\xa0mg once daily [QD]) and BIN (45\xa0mg twice daily [BID]) as dose level (DL) 0. Reduction of the ENC and BIN doses (300\xa0mg QD and 30\xa0mg BID at DL-1\xa0and 200\xa0mg QD and 30\xa0mg BID at DL-2) was preplanned in case of ≥2 dose-limiting toxicities (DLTs). Primary objectives were to estimate the recommended phase II dose\xa0of the triplet combination, DLT and safety. As per the sponsor s decision, the study was terminated after the phase I part, as the clinical efficacy of the combination is currently being investigated in a pivotal, placebo-controlled (PEM mono), double-blinded phase III trial (STARBOARD,NCT04657991).\n\n\nRESULTS\nFifteen patients were enrolled. DLTs of DL0 were creatine phosphokinase (CPK) elevation plus cytokine release syndrome (n\xa0=\xa01)\xa0and gamma glutamyl transferase (GGT) increase (n\xa0=\xa01). No DLT was observed in further 3\xa0+\xa03 patients at DL-1. One (isolated GGT elevations) DLT of DL0 was questionable, as the patient had further episodes of isolated GGT elevations after treatment discontinuation. Hence, further 6 patients were enrolled at DL0: here, no DLT occurred. In total, 13 of 15 patients (87%) experienced a treatment-related adverse event (TRAE) and 8 patients (53%), a grade ≥III TRAE; there were no TRAE-related deaths. Increases in aspartate aminotransferases, GGT (6/15 patients) and CPK elevations (4/15) were the most common grade III-IV TRAE. In median, patients received triplet therapy for 24 weeks (interquartile range [IQR], 12-45). Of the 14 patients evaluable for efficacy, the overall response rate was 64% (95% confidence interval [CI], 35-87). At a median follow-up of 25 months (IQR, 9-28), progression-free survival at 12 months was 41% (95% CI, 13-68).\n\n\nCONCLUSIONS\nTriplet therapy with PEM, ENC and BIN as used in the study was feasible and safe and led to clinically meaningful disease control.